Erectile dysfunction (ED) is increasing in prevalence with the ageing of society and with greater numbers of patients suffering from diabetes, which are risk factors for its development. The impact of ED on quality of life of patients is generally underestimated, but its significance to patients can be demonstrated by the huge market for currently available treatments. My laboratory recently reported that the Vcsal transcript (variable coding sequence protein a1) is one of the most down regulated genes in the corpora of rats in three models of ED; diabetic, age-related and neurogeniic. We therefore proposed that Vcsal could be a potential marker for organic ED. In addition, gene transfer of plasmids expressing Vcsal increased erectile function in ageing rats and higher amounts of plasmid caused priapism, suggesting a direct role of the Vcsal gene in erectile physiology. We also recently demonstrated that the mature peptide product of Vcsal, sialorphin, can directly restore erectile function in the ageing rat. This has led us to propose the hypothesis that Vcsal is essential for normal erectile function, that reduced expression results in ED and overexpression results in priapism. This hypothesis will be tested by gene transfer of plasmids expressing Vcsal into the corpora of diabetic animals with ED, and determining if this improves erectile function, or higher amounts causes priapism. In addition we will perform in vivo knockdown experiments of Vcsal in rats using adenovirus siRNA technology to determine if down regulation of Vcsal causes ED. We will also investigate the ability of sialorphin to directly restore erectile function. Recent publications by my group and others have shown that sialorphin is an efficient physiological antagonist of neutral endopeptidase (NEP). We hypothesize that the action of sialorphin as an NEP inhibitor induces relaxation of the smooth muscle tissue of corpora and thereby improves erectile function. Higher amounts of NEP inhibition may lead to priapism. We will perform studies of corporal smooth muscle strips in vitro to determine if inhibition of NEP can induce smooth muscle relaxation, and if NEP inhibition in ageing rats improves erectile function. We will also investigate if overexpression of Vcsal activates biochemical pathways associated with priapism. There is a human homoiogue of Vcsal (hSMRSA) which we hypothesize has a similar physiological role in humans. We will determine if hSMRSA is downregulated in the corpora of patients with ED and confirm that hSMRSA has the same effects on erectile function in rats as Vcsal. These studies will provide insight into the physiology and pathophysiology of erectile function and may suggest novel targets for treating smooth muscle diseases, such as ED and priapism and other vascular diseases. Vcsal/hSMR3A expression might also be used as a non-subjective marker of erectile function. [unreadable] [unreadable] [unreadable]